We showed recently in a murine model of cutaneous leishmaniasis combining two main features of natural transmission, low parasite dose and inoculation into a dermal site, that CD8+ T cells play an essential role in immunity to primary and secondary infection with L. major in the skin. In co-cultures in vitro, infected dendritic cells (DC) induced the release of IFN-gamma by purified primed CD8+ T cells, indicating that DC can efficiently process exogenously delivered antigen for presentation by major histocompatibility complex (MHC) class I molecules. In this study we address the mechanisms by which the OVA257-264 peptide (SIINFEKL), expressed as part of the 3'nucleotidase (NT-OVA) by transfected L. major parasites, is processed by infected DC and presented to TCR transgenic OT-I CD8+ T cells. Inoculation of L. major NT-OVA parasites in the ear dermis of congenic mice specifically induce the proliferation of transferred naive OT-I CD8+ T cells in the draining lymph nodes. In co-cultures in vitro, L. major NT-OVA-infected DC induce the proliferation of purified naive OT-I CD8+ T cells as well as IFN-gamma secretion. We further demonstrated that presentation of SIINFEKL by L. major NT-OVA-infected DC is TAP1-independent, suggesting that cross-priming of leishmania-specific CD8+ T cells does not involve cytosolic processing and ER translocation of exogenous antigens. We extended this latter observation to wild-type L. major antigen cross presentation, suggesting that in the case of Leishmania, peptide ligands are generated and loaded onto Class I in the phagosome. The conditions favoring the persistence of low numbers of parasites in the skin following healing in resistant mice has been further studied, and has been extended to studies in normally resistant mice that fail to heal certain strains of L. major, and to normally susceptible BALB/c mice that fail to control certain strains of L. major even in the absence of IL-4 receptor signalling. In each case, the failure to eliminate prasites from the skin is related, at least in part, to production of IL-10 by CD4+CD25+ regulatory T cells that home to and/or are expanded at the site of infection. Parasite clearance can in each case be achieved by treatment with anti-IL-10R or anti-CD25, which also results in a dramatic up-regulation of the number of IFN gamma producing cells in the site. Mice that achieved sterile cure as a consequence of anti-IL-10 receptor antibody treatment were no longer immune to reinfection. Since individuals with healed lesions have life long immunity to reinfection, vaccination using virulent L. major promastigotes, termed leishmanization, remains the gold standard in terms of the potency and durability of acquired immunity that can be achieved, but remains problematic because of the severity of the vaccination-lesions. In an attempt to develop a leishmanization protocol that minimizes pathology while maintaining long term protection, live parasites were co-injected with CpG-containing immunostimulatory oligodeoxynucleotides (CpG ODNs). C57Bl/6 mice infected intradermally using L. major/CpG ODN developed little or no dermal lesions and showed an early containment of parasite growth. The CpG ODNs provoked a transient inflammation that included an early recruitment and accumulation of IFN-g?producing CD4+ lymphocytes in the site. Attenuation of the live vaccine did not compromise its ability to confer long-term immunity, as mice receiving L. major/CpG ODN were totally protected against re-infection with L. major for up to 6 months. Our results suggest that immune-modulation using CpG ODNs might be a practical approach to improving the safety of a highly effective live vaccine that has already been widely applied.